2013 ASCB Annual Meeting, 2013, 02, 34─34

Ethanol consumption inhibits Glucokinase Tranional activation through ATF3-PDX-1-HDAC1 axis and leads to pancreatic β-cell dysfunction and apoptosis.

JiYeon Kim, Keon Jae Park, Dae Yeon Lee, Gyu Hee Kim, Eun Ae Jeong, Won-Ho Kim

Abstract

Previously, we demonstrated that chronic alcohol consumption induced pancreatic β-cell dysfunction through glucokinase (GCK) nitration and its downregulation, thus leading to impaired glucose tolerance and insulin resistance; however, little is known about the exact mechanisms underlying chronic alcohol consumption-induced GCK downregulation. . Here, we found that pancreatic β-cells of ethanol fed-mice exhibited a decrease in GCK mRNA and protein, and an increase in activating tranion factor 3 (ATF3), which were determined by ethanol metabolism pathway. We also identified the putative ATF3 binding sites located between -287-bp and -158-bp of GCK promoter as the repressor region associated with ethanol-mediated GCK downregulation. ATF3 inhibitory effects on GCK tranional activity were remarkably attenuated by site- or deletion-mutagenesis in the region containing ATF3-binding site, especially between -186 and -173-bp. ChIP assay also shows that ATF3 inhibits GCK promoter activity via a direct recruitment to GCK promoter region spanning from -287 to -158. Furthermore, ATF3 directly interacts with PDX-1 and thus inhibits the association of PDX-1 with p300, a histone acetytransferase, resulting in a potent downregulation of GCK tranional activity. Likewise, ethanol-induced ATF3 enhanced the deacetylation of histone H3 and chromatin remodeling of GCK depended on ATF3-induced HDAC1/2 activation. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA ameliorates ethanol-mediated β-cell dysfunction and apoptosis through the restoration of PDX-1-mediated GCK tranional activity. Collectively, we propose a mechanism for ethanol consumption-induced ATF3 plays as a negative upstream regulator of GCK tranional activity and thus promotes pancreatic β-cell dysfunction.

• 본 연구는 질병관리본부 연구개발과제(과제번호 2011-NG64001-00) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2011-NG64001-00) by Research of Korea Centers for Disease Control and Prevention.